Pretreatment Deoxycytidine Kinase Levels Predict in Vivo Gemcitabine Sensitivity 1 Supported by Eli Lilly & Co, International and The Netherlands.1

• Published in: Molecular cancer therapeutics 2002-04, Vol.1 (6), p.371
• Main Authors: Judith R. Kroep, Willem J. P. Loves, Clasina L. van der Wilt, Enrique Alvarez, Iannis Talianidis, Epie Boven, Boudewijn J. M. Braakhuis, Cornelis J. van Groeningen, Herbert M. Pinedo, Godefridus J. Peters
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514

Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine (2′,2′-difluorodeoxycytidine), a deoxycytidine analogue active against various solid tumors. Cytidine deaminase (CDA) catalyzes the degradation of gemcitabine. We determined whether dCK and/or CDA levels would predict response to gemcitabine. Activities of dCK and CDA were measured in a panel of eight gemcitabine-sensitive and -resistant tumors of a different origin (pancreas, lung, colon, ovary, and head and neck) grown as s.c. tumors in mice. Sensitivity to gemcitabine was expressed as treated versus control (tumor volume treated mice/control mice). Gemcitabine was given on days 0, 3, 6, and 9 (q3dx4) at its maximum tolerated dose. In addition, we measured the mRNA expression and protein levels of dCK in seven human tumor xenografts. dCK activity (mean ± SE) ranged from 3.3 ± 0.3 to 18.4 ± 1.2 nmol/h/mg protein. Sensitivity to gemcitabine, expressed as treated versus control, ranged from 0.98 to 0.02, and the activity of CDA varied from 2 ± 2 to 411 ± 4 nmol/h/mg protein. In contrast to CDA, dCK activity was clearly related to gemcitabine sensitivity (ρ = −0.93; P < 0.001). This indicates that dCK might be an important prognostic marker for gemcitabine sensitivity. Protein levels were significantly related to both dCK activity ( r = 0.96; P < 0.001) and gemcitabine sensitivity (ρ = −0.96; P < 0.001). dCK expression as determined by competitive template reverse transcriptase PCR was significantly related with the dCK activity ( r = 0.88; P = 0.025) and protein levels (ρ = 0.80; P = 0.052) but not with gemcitabine sensitivity, suggesting a post-translational regulation of dCK. In conclusion, the clear correlation between dCK levels and gemcitabine sensitivity in various murine tumors and human tumor xenografts may be a prognostic parameter when considering gemcitabine therapy.